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DOI: 10.1055/s-0031-1290103
An Expedient Route to 3-Methoxy-2-furaldehyde
Publikationsverlauf
Publikationsdatum:
09. Dezember 2011 (online)
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Abstract
An expedient route to 3-methoxy-2-furaldehyde is presented.
Key words
furans - aldehydes - heterocycles - nucleophilic substitution - Diels-Alder reaction
- 1 For a review, see:
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Mesiter C.Scharf H.-D. Synthesis 1981, 733 -
3c
Mesiter C.Scharf H.-D. Synthesis 1981, 737 -
4a
Ly ND.Schlosser M. Helv. Chim. Acta 1977, 60: 2085 -
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References and Notes
Two of the major impurities were tentatively assigned using HPLC-MS and ¹H NMR as a dimer and trimer likely resulting from side reaction of the starting material with the product.
6
General Experimental:
All reactions were performed under a nitrogen atmosphere. ¹H
NMR spectra were recorded using an Oxford ASR400 spectrometer operating
at 400 MHz at a probe temperature of 25 ˚C. Assays by HPLC-MS
analyses were performed on an Agilent 1200 using a Zorbax C18 column
and H2O-MeCN mobile phases that included 0.1% formic
acid. 3-Bromofuran was obtained from Penn Specialty Chemicals and
was separated from aqueous materials included for stabilization
before use. All commercially available starting materials, reagents
and solvents were used as received.
Preparation
of 3-Bromo-2-furaldehyde: To a 5-L, 4-neck round-bottomed flask
was charged 2-methyltetrahydrofuran (1000 mL) followed by i-Pr2NH (173 mL, 1.3 equiv).
The mixture was cooled to T
i
= -10 ˚C
and n-BuLi (410 mL, 2.5 M in hexanes,
1.0 equiv) was charged into a 1-L addition funnel. The n-BuLi was added dropwise to the reactor
over 15 min while keeping the batch temperature below -10 ˚C. The
resulting pale yellow solution was cooled to -45 ˚C
and kept for 10 min at that temperature. 3-Bromofuran (neat, liquid,
150 g) was charged while maintaining batch tempera-ture below -40 ˚C.
The dark brown suspension was stirred at -45 ˚C
for 30 min and DMF (108 mL, 1.4 equiv) was added dropwise over 10
min via addition funnel while observing an exotherm. Temperature
was maintained below -40 ˚C during addition. The
reaction was completed after 10 min at -40 ˚C
and the batch was quenched by the addition of 25% citric
acid solution (1500 mL, w/v). The layers were separated
and the aqueous layer was extracted once with EtOAc (1000 mL). The
combined organics were subse-quently washed with H2O
(500 mL) and then with sat. aq NaCl (500 mL). The organic layer
was concentrated under reduced pressure at 30 ˚C to give
a dark brown oil (178 g) along with some visible solids. The residue
was diluted with MTBE (100 mL) and filtered through a medium fritted funnel.
An additional portion of MTBE (100 mL) was used to wash the filter.
The filtrate was concentrated to give 3-bromo-2-furaldehyde (164
g, 92%) as a dark brown oil.
Analytical data were
in accordance with those of a commercial sample.
Preparation of 3-Methoxy-2-furaldehyde:
To a 50-L reactor equipped with an overhead stirrer, nitrogen inlet
and reflux condenser was added anhyd MeOH (20 L) followed by NaOMe
(25 mL, 25 w/w% solution in MeOH) to assure a
basic media at start of addition. The solution was heated to T
i
= 64 ˚C. 3-Bromo-2-furaldehyde
(1034 g) was charged to a 1-L addition funnel and NaOMe (5 L, 25
w/w% in MeOH, 3.7 equiv) was charged into a second
funnel. The NaOMe and 3-bromofurfural in the respective addition
funnels were simultaneously added dropwise over 5 h, and the mixture was
subsequently stirred at 64 ˚C for 13 h. After the reaction was
complete, the mixture was cooled to 20 ˚C and stirred at that
temperature for 3 h. The temperature was lowered further to -30 ˚C
and 12% aq AcOH (10 L) was added resulting in a rise of
the temperature to about 5 ˚C. Most of the MeOH (about
23 L) was removed at reduced pressure at 35 ˚C and the
remaining mixture (about 12 L) was extracted with CH2Cl2 (2 × 10
L). The combined organics were washed with half-saturated aq NaHCO3 (10
L). The organics were concentrated at reduced pressure at 25 ˚C
to give a black crystalline material. Reslurry in MTBE (4 L) and hexane
(4 L) gave about 250 g of product as filterable solids. Additional
material (260 g of black amorphous material which was stuck to the
flask) along with 120 g from evaporation of the mother liquors was
combined, dissolved in CH2Cl2 (1.5 L) and
passed through silica gel (500 mL) which was further eluted with
1.5 L CH2Cl2. The CH2Cl2 was
evaporated and the resulting solids were combined with the first
solids (250 g) followed by suspending the solids in MTBE (3 L).
Hexanes (3 L) were then added over 5 h at r.t. After stirring for
an additional 17 h the slurry was cooled to 0 ˚C. The solids
were collected by filtration and provided after drying 3-MeO-2-furaldehyde
(440 g, 59%) as a brown solid.
Analytical data
were in accordance with those described in the literature.²c